ABSTRACT

Context Early-onset alcoholism differs from late-onset alcoholism by its association
with greater serotonergic abnormality and antisocial behaviors. Thus, individuals
with early-onset alcoholism may be responsive to treatment with a selective
serotonergic agent.

Objective To test the hypothesis that drinking outcomes associated with early
vs late-onset alcoholism are differentially improved by the selective 5-HT3 (serotonin) antagonist ondansetron.

Design Double-blind, randomized, placebo-controlled clinical trial.

Settings University of Texas Health Science Center in Houston (April 1995-June
1998) and University of Texas Health Science Center in San Antonio (July 1998-December
1999).

Main Outcome Measures Self-reported alcohol consumption (drinks per day, drinks per drinking
day, percentage of days abstinent, and total days abstinent per study week);
and plasma carbohydrate deficient transferrin (CDT) level, an objective and
sensitive marker of transient alcohol consumption.

Results Patients with early-onset alcoholism who received ondansetron (1, 4,
and 16 µg/kg twice per day) compared with those who were administered
placebo, had fewer drinks per day (1.89, 1.56, and 1.87 vs 3.30; P = .03, P = .01, and P = .02, respectively) and drinks per drinking day (4.75, 4.28, and
5.18 vs 6.90; P = .03, P
= .004, and P = .03, respectively). Ondansetron,
4 µg/kg twice per day, was superior to placebo in increasing percentage
of days abstinent (70.10 vs 50.20; P = .02) and total
days abstinent per study week (6.74 vs 5.92; P =
.03). Among patients with early-onset alcoholism, there was a significant
difference in the mean log CDT ratio between those who received ondansetron
(1 and 4 µg/kg twice per day) compared with those who received the placebo
(−0.17 and −0.19 vs 0.12; P = .03 and P = .01, respectively).

Conclusion Our results suggest that ondansetron (particularly the 4 µg/kg
twice per day dosage) is an effective treatment for patients with early-onset
alcoholism, presumably by ameliorating an underlying serotonergic abnormality.

We were the first, to our knowledge, to show that pretreatment with
the selective 5-HT3 receptor antagonist ondansetron attenuates
low-dose alcohol–induced positive, subjective effects and the "urge
to drink" in humans.20,21 Swift
et al,22 using higher alcohol and ondansetron
dosages, found that ondansetron pretreatment decreased alcohol preference.
However, a mixture of stimulant and sedative interactions between ondansetron
and alcohol were also reported. In contrast, Doty et al23
found that ondansetron did not alter alcohol-induced mood, presumably because
using intravenous rather than oral ondansetron and a group rather than an
individual experimental setting reduced the sensitivity of their mood assessments.

In a preliminary 6-week, double-blind study of 71 patients not severely
dependent on alcohol, 0.5 mg/d but not 4 mg/d of ondansetron was almost superior
to placebo (P = .06) at reducing alcohol consumption.24 These results strengthened the rationale for testing
ondansetron's efficacy in treating alcoholism within a larger-scale trial
but raised also the possibility that ondansetron's dose-response curve was
an inverted U-shape.

Psychopathological factors distinguish alcoholic subtypes based on course,
prognosis,25- 27
and differential treatment response. Alcoholic patients with early onset compared
with late onset develop problem drinking earlier, exhibit a broad range of
antisocial behaviors, and have a higher predisposition toward alcoholism.
High concordance between age of onset and other hypothetically-derived28,29 and empirically-driven typologies26,30 validated age of onset for a priori
segregation of alcoholic subtypes in a recent trial.31

Solid evidence exists that an early compared with late alcoholism onset
is associated with serotonergic dysfunction.32- 38
While this 5-HT dysfunction among patients with early-onset alcoholism has
been hypothesized to be a deficient state,39,40
newer evidence implicates the interaction between chronic drinking and mechanistic
processes regulating serotonergic function.

Our double-blind, randomized, placebo-controlled clinical trial tested
the hypothesis that patients with early-onset alcoholism compared with late-onset
alcoholism (classified a priori), would experience better drinking outcomes
in response to ondansetron treatment due to the amelioration of serotonergic
dysfunction. We examined ondansetron's dose-dependent effects by testing a
16-fold dose range (ie, 1, 4, and 16 µg/kg twice per day) encompassing
those used in a previous clinical trial.24

METHODS

Subjects

The 321 enrollees (70% male; 78.6% white) were diagnosed as having alcoholism
by the Diagnostic and Statistical Manual of Mental Disorders,
Revised Third Edition.41 Enrollees were
25 to 65 years old; scored more than 5 on the Michigan Alcoholism Screening
Test,42 which assessed the severity of alcohol-related
problems; reported drinking 3 or more standard drinks per day during the telephone
screening; and had a negative urine toxicological screen for narcotics, amphetamines,
or sedative hypnotics at enrollment. Abstinence was not a study entry criterion;
however, participants reported a desire to stop drinking and to participate
in psychosocial treatment. Exclusion criteria were a current psychiatric diagnosis
other than alcohol or nicotine dependence; alcohol withdrawal symptoms necessitating
inpatient detoxification; clinically significant abnormalities (ie, on physical
examination, electrocardiographic recording, hematological evaluation, or
elevated bilirubin levels); pregnancy; lactation; taking medications with
a potential effect on alcohol consumption; mandated incarceration or employment
loss for not receiving alcoholism treatment; and receipt of alcoholism treatment
30 days prior to enrollment. Ethics approval was provided by the Committee
for the Protection of Human Subjects, Health Science Center, University of
Texas, Houston. Subjects were recruited by newspaper or radio advertisement.

General Procedures

All testing took place at the University of Texas Health Science Center
in Houston between April 1995 and June 1998. Data was analyzed at the University
of Texas Health Science Center in San Antonio between July 1998 and December
1999. At enrollment (visit 0), after providing written, informed consent,
we assessed subjects on (1) physical health, which included a medical history
and physical examination, vital signs (ie, blood pressure, pulse, and temperature),
12-lead electrocardiogram, and laboratory studies including a urine pregnancy
test; (2) breath alcohol concentration (BAC); (3) urine drug and biochemical
screens; (4) psychiatric diagnosis, which included a Structured Clinical Interview
for DSM-III-R43,44;
(5) age of onset, which was determined using item B 28 of the Comprehensive
Drinking Profile45; (6) the Michigan Alcoholism
Screening Test42; (7) addiction severity, which
was assessed using the Addiction Severity Index46;
(8) self-reported drinking based on a timeline follow-back (TLFB) over the
past 90 days47; (9) objective quantification
of alcohol consumption using the sensitive and specific marker, plasma carbohydrate
deficient transferrin (CDT) level48- 51;
and (10) an assessment of alcohol withdrawal symptoms assessed by the revised
Clinical Institute Withdrawal Assessment (CIWA-Ar) scale.52
Eligible subjects were invited back to the clinic at visit 1, following a
review of the hematological, biochemical, and urine tests, in which they received
the single-blind placebo for 1 week and attended their first cognitive behavioral
therapy (CBT) session.

From visits 3 through 12, subject assessment included weekly vital signs,
BAC, TLFB, CIWA-Ar, an adverse event profile, concomitant medications, pill
count, percentage of urine riboflavin (an inert tracer for assessing medication
compliance), and psycho-social treatment attendance outside the study. At
visits 4, 8, and 12, subjects received a plasma CDT measurement; an electrocardiogram;
a urine pregnancy test; hematological, biochemical, and urine drug screens.
Subjects were expected to attend weekly CBT sessions throughout the study
period. At visit 12 (study end), a physical examination and the hematological
and biochemical checks were repeated to establish health status (Figure 1). Visits were interspersed by a
period of 1 study week, which was a maximum of 11 days (from Monday of the
previous week to Friday of the current week).

Patients diagnosed as having early-onset and late-onset alcoholism
were similar in number, age, sex, and drinking level at enrollment. Trial
completers were those patients who completed all 11 double-blind visits or
10 double-blind visits plus the final physical health evaluation.

Supply, Dosages, Blinding, and Compliance for Medication

Ondansetron, obtained from Glaxo-Wellcome Inc as 8-mg tablets ($19.50/tablet),
was compounded and dispensed using procedures approved by the Food and Drug
Administration under investigational new drug No. 45,228. Crushed ondansetron
tablets (1, 4, and 16 µg/kg twice per day) were packed into opaque size
1 gelatin capsules (Shinogi Qualicaps SA, Madrid, Spain) with cornstarch filler.
Placebos were opaque gelatin capsules of the same size, shape, and color containing
cornstarch. Body weight categories were used for the microgram per kilogram
dosing procedure (mean [SD] ondansetron dosages taken vs those assigned were
0.99 [0.02] vs 1.00, 4.00 [0.05] vs 4.00, and 16.18 [0.38] vs 16.00 µg/kg
twice per day, which is equivalent to 0.15, 0.63, and 2.56 mg/d, respectively
based on mean body weight). Medication was packaged with the inert tracer
(a 50-mg crushed riboflavin tablet),53,54
and dispensed in bottles labeled with identification, study and visit numbers,
and the date. The returned medication bottle at each weekly visit was used
to calculate the pill count.

Ultraviolet fluorescence of the subjects' urine samples were compared
against a background control sample that contained 7 µmol of riboflavin
per milliliter using an AMINCO-Bowman spectrofluorimeter (Spectronic Unicam,
Rochester, NY) with an excitation wavelength of 464 nm and an emission wavelength
of 530 nm. The relative optical density of the riboflavin control sample was
set at a high cut-off point (70%) and the samples were read as a percentage
of optical density (a percentage of urine riboflavin).

Cognitive Behavioral Therapy

Cognitive behavioral therapy, an integration of cognitive behavioral
and social learning theory, enables alcoholic patients to achieve and maintain
abstinence by enhancing their ability to manage high-risk situations, which
can trigger alcohol-seeking behavior.55,56
All study patients received standardized CBT in groups of up to 8 individuals
using the Cognitive Behavioral Coping Skills Therapy57 manual, and selected exercises from Treating Alcohol Dependence: A Coping Skills Therapy Guide.58

Statistical Analysis

Data quality was supervised by a database coordinator and statistician.
Individual subject plots were checked for unusual values and completeness.
Efficacy values were validated as correct against the case records. Data were
analyzed using SAS statistical software.59

Efficacy variables were self-reported alcohol consumption from visit
3 through 12 using the TLFB (drinks per day, drinks per drinking day, percentage
of days abstinent, and total days abstinent), and plasma CDT level, which
is an objective measure of drinking, at visits 4, 8, and 12. Treatment compliance
measures were study attendance rate and medication compliance (both pill count
and percentage of urine riboflavin). Physical health and safety measures were
BAC at clinic attendance; CIWA-Ar; vital signs; hematological, biochemical,
and urine drug screens; use of concomitant medications; attendance at psycho-social
treatments outside the study; and adverse events profile.

Subjects' data were analyzed as randomized using an urn60
procedure after the screening visit. Subjects did not receive their randomized,
double-blind study medication (ie, ondansetron or placebo) until the end of
the 1-week single-blind placebo period (at visit 2). The first recorded response
to medication was, therefore, not measured until the end of the first week
of double-blind treatment (visit 3). Response to the double-blind study medication
treatment was, therefore, measured from visits 3 to 12 and all subjects randomized
were included in the efficacy analyses,61 irrespective
of whether they completed the study. Previous visit values of outcome measures
(before visit 3) were used as covariates to control for study entrance and
placebo pill taking effects.62

Alcoholic patients with early vs late onset developed alcoholism at
25 years or younger and older than 25 years, respectively. Subjects were randomly
assigned to 1 of the 4 dosage groups (placebo, or ondansetron 1, 4, or 16
µg/kg twice per day) after balancing based on age of onset, sex, and
the average intake drinking level (drinks per day). The 2 × 4 factorial
study design examined age of onset (patients with early-onset vs late-onset
alcoholism) and medication dosage (placebo, or ondansetron 1, 4, and 16 µg/kg
twice per day), and their interaction. Treatment response was measured over
visits 3 to 12 (10 double-blind visits using the TLFB technique) after adjusting
for differences in study entrance, study enrollment effect (visit 1), and
placebo pill taking effect (visit 2).

Counts and/or percentages for categorical items were compared among
groups with the χ2 test for independence when measured at either
1 time or accumulated over multiple time points. Continuously distributed
data were reported as mean (SE) for raw measures or as mean change (SE) from
baseline (visit 2) for calculated outcome measures, and as 95% confidence
intervals (CIs) for mean response from the primary efficacy analyses.

If a 2-way analysis of variance at visits 0, 1, or 2 was significant
either for the age of onset or dosage main effects or their interaction, then
the groups were unequal on that measure and the baseline values (study entry,
visits 1 or 2) were included as a covariate in the efficacy analysis to adjust
for these differences. Covariate values from other visits were excluded if
they were not significantly related to outcome and did not reduce variability
by controlling for individual study entrance and placebo pill taking effects.
These covariates removed the study entrance and placebo pill taking effects
from the double-blind efficacy response. Any covariate for inclusion in the
final model was tested for its interaction with the age of onset, dosage groups,
and their interaction. Additionally, covariates were plotted against the residuals
to determine their random normal distribution. In all cases, these plots showed
significant covariates to be linear and resulted in valid analyses.

As a data reduction technique, self-reported drinking response was calculated
as the mean of visits 3 through 12. This average response analysis preserved
sample size since all subjects with at least one outcome measure (ie, any
of visits 3-12) were included in the efficacy analysis. Since these means
have a variance inversely proportional to the number of visits attended,63 the outcome analysis was weighted by the number of
visits. The residuals of this 2-way analysis of covariance, weighted for missing
data effects, were checked for normality by computing their skewness, kurtosis,
and homogeneity of variance by histogram plots and against the predicted outcome.
When needed, standard transformations (eg, square root for percentages or
the log when residual variability increased with response) were used to satisfy
the assumptions of the analytic procedure. The objective drinking marker,
plasma CDT, was analyzed using a similar statistical strategy to the self-reported
measures except that enrollment was used as the baseline (CDT was only obtained
monthly) and response was calculated over the monthly visits (ie, 4, 8, and
12) as an average log ratio with enrollment values. Type I errors were minimized
by conducting only a priori pairwise dosage comparisons within the patient
groups with early-onset or late-onset alcoholism when there was a main effect
of ondansetron or an interaction between age of onset and treatment dosage.

RESULTS

Study Sample

Patients with early-onset and late-onset alcoholism were equally represented,
and had similar levels of self-reported and objective drinking within the
cohort. Alcoholic patients with early compared with late onset were younger,
of lower social class, more severely addicted with a longer history of alcoholism,
and had higher rates of antisocial personality disorder (Table 1). There was no significant interaction between age of onset
and treatment dosage for any of the intake variables except for drinks per
day, which was addressed by the analysis of covariance. By visit 2 (start
of the double-blind period), all 8 groups had similar drinking levels.

Efficacy Measures

Among patients with early-onset alcoholism, ondansetron (1, 4, and 16
µg/kg twice per day) compared with placebo, significantly reduced self-reported
drinking. For patients with early-onset alcoholism, significant improvements
between the start of the double-blind response period (visit 3) and study
end were seen on (1) all drinking measures for those who received 4 µg/kg
of ondansetron twice per day and (2) percentage of days abstinent and total
days abstinent for those who received 16 µg/kg of ondansetron twice
per day. In contrast, only the placebo and 16 µg/kg ondansetron group
patients with late-onset alcoholism had significantly improved drinking outcomes
during double-blind treatment (Figure 2).

Data are responses observed at the start of double-blind (visit 2)
and the mean outcome observed during study (mean of visits 3-12). Analyses
refer to pairwise comparisons between the ondansetron treatment groups and
placebo. The a* and a† represent significant differences between an
ondansetron dosage and placebo groups at the 5% and 1% levels, respectively.
The b* and b† denote significant differences within a given treatment
group from the start of the double-blind response period to the outcome during
study at the 5% and 1% levels, respectively.

There was a significant interaction between age of onset and treatment
dosage on the self-reported drinking variables of drinks per day (F3,245 = 3.65; P = .01); drinks per drinking day
(F3,174 = 3.17; P = .03); percentage of
days abstinent (F3,237 = 2.9; P = .04),
and total days abstinent (F3,237 = 2.9; P
= .04). Patients with early-onset alcoholism who received dosages of ondansetron
of 1, 4, or 16 µg/kg twice per day reported significantly lower numbers
of drinks per day or drinks per drinking day compared with those who received
placebo. Also, patients with early-onset alcoholism who received ondansetron
4 µg/kg twice per day, compared with placebo, had more percentage of
days abstinent and total days abstinent. Effect sizes were as follows for
drinks per day, drinks per drinking day, percentage of days abstinent, and
total days abstinent for (1) 1 µg/kg of ondansetron twice per day: 0.26,
0.25, 0.13, and 0.06; (2) 4 µg/kg of ondansetron twice per day: 0.37,
0.41, 0.26, and 0.24; and (3) 16 µg/kg of ondansetron twice per day:
0.22, 0.23, 0.17, and 0.18. Effect sizes of 0.2, 0.5, and 0.8 are small, medium,
and large, respectively.64

On the objective drinking measure (plasma CDT), there was a main effect
during the study on the mean log CDT ratio (F3,177 = 3.15; P = .03). Among patients with early-onset alcoholism, the
mean log CDT ratio was significantly reduced when ondansetron dosages 1 and
4 µg/kg twice per day were compared with placebo (Figure 3). For patients with early-onset alcoholism, effect size
on mean log CDT ratio for the ondansetron 1, 4, and 16 µg/kg twice per
day dosages were 0.55, 0.58, and 0.21, respectively. While there was a decrease
in mean log CDT ratio for groups of patients with late-onset alcoholism, none
of the ondansetron dosage groups were superior to placebo.

Mean log CDT ratio was the mean log CDT at a given visit (ie, 4,
8, or 12) divided by the mean log CDT at enrollment. The dagger indicates P<.01 and the asterisk indicates P<.05.

Our results yielded a significant effect on 5 response variables related
to actual drinking measures. The probability of making a type I error on any
1 to all 5 ranges from .05 to less than .001. A factor analysis of cases for
all 5 ranges indicates 2 dimensions; so for any 2 independent comparisons,
the type I error rate is less than .0025. Even when all baseline measures
related to outcome were used in the model,62
rather than just the confounding61 baseline
measures, the results were similar. For example, the interaction between patients
with early-onset and late-onset alcoholism receiving ondansetron was significant
for drinks per day (P = .006) with the patients with
early-onset alcoholism in the ondansetron 4 µg/kg twice per day dosage
group being superior to placebo (P<.001).

Physical Health and Safety Measures

No serious adverse events occurred. Adverse event rates were similar
for the ondansetron and placebo groups, and required no supervised medical
intervention. The most common adverse events by organ system for the ondansetron
vs placebo dosages were central nervous system (headache), 3.4% vs 4.2%; gastrointestinal
tract (constipation), 5.0% vs 1.4%; cardiovascular (tachycardia), 0.3% vs
0.0%; skin (rash/pruritis), 2.2% vs 2.8%; and others, 1.8% vs 1.0%. One fatality
unrelated to the study medication occurred due to the subject falling down
a flight of stairs at home.

Positive BACs were rare (mean, .01%) with no difference between patients
with early-onset and late-onset alcoholism. Alcohol withdrawal symptoms were
infrequent (mean [SE] for CIWA-Ar, 2.8 [0.25] and 2.5 [0.23]; patients with
early-onset and late-onset alcoholism, respectively). Testing positive for
1 or more of 9 agents in the urine drug screen was similar for patients with
early-onset (15.5%) and late-onset alcoholism (15.6%). Drug use frequencies
for patients with early-onset vs late-onset alcoholism were 44% vs 29% for
marijuana; 24% vs 19% for cocaine; 16% vs 26% for opiates; and 16% vs 26%
for benzodiazepines. Rates of concomitant medication use and of psychosocial
attendance outside the study were similar for patients with early-onset (13.6%
and 4.9%) and late-onset alcoholism (14.4% and 4.3%).

COMMENT

Ondansetron significantly reduced alcohol consumption and increased
abstinence among patients with early-onset but not late-onset alcoholism.
A dosage of ondansetron of 4 µg/kg twice per day was most efficacious;
however, its superiority over the other ondansetron dosages was statistically
insignificant. We did not detect an inverted U-shaped dose-response curve
for ondansetron among patients with early-onset alcoholism; however, increased
efficacy at higher dosages appears unlikely. Limitations of a short treatment
period and the inclusion of only white males in the Sellers et al24 study precluded direct comparison with this study.
Nevertheless, finding ondansetron efficacious among patients with early-onset
alcoholism is not inconsistent with their observation24
that excluding heavy drinkers (ie, >10 drinks per day) rendered ondansetron-related
drinking reductions compared with placebo statistically significant as this
procedure simply decreased variance in their smaller sample size study.

Abstinence at enrollment was not a study entry requirement but the treatment
goal. Enrolling actively drinking alcoholic patients represented a more naturalistic
point related to when help was sought. By not requiring an abstinence period
at enrollment, the potential for postcessation rebound into drinking was reduced.
Yet, abstinence rate for the 4 µg/kg of ondansetron twice per day group
among patients with early-onset alcoholism was relatively high (about 70%).
Exploratory analyses indicated that ondansetron's antidrinking effects did
not differ between abstainers and active drinkers at the start of double-blind
analysis (data not shown). Consistently, the visit 2 baseline covariate was
not needed in our full analyses; thus, drinking status was not a determinant
of ondansetron response. Ondansetron does not alter alcohol pharmacokinetics65; hence, its utility in actively drinking alcoholic
patients was an additional therapeutic benefit.

Participants nearly halved their drinking between enrollment and the
end of the lead-in, single-blind placebo period. Emphasis on drinking quantification
probably evoked self-regulatory measures. The single-blind placebo, lead-in
period enabled measurement of how the psychological effect of pill taking
contributed to the overall treatment response. Promise or delivery of psychosocial
treatment might also have improved drinking outcomes. Since all subjects received
CBT, it was impossible to discern if, and by how much, psychotherapy type
or intensity would interact with ondansetron treatment response, or whether
psychotherapy alone is sufficient in treating patients with late-onset alcoholism
due to their limited disease predisposition.

We discounted the remote possibility that ondansetron's effectiveness
among ondansetron-receiving patients with early-onset alcoholism was due to
a less pronounced placebo effect in those who received placebo. The placebo
lead-in period should have controlled for any differential placebo effects.
Extensive exploratory analyses of all data collected in this trial revealed
no significant baseline outcome predictor that would selectively impair drinking
behavior among patients with early-onset alcoholism who received placebo compared
with the ondansetron recipients. Patients with early-onset alcoholism in treatment
groups were similar on baseline drinking measures and psychosocial characteristics.
Hence, among patients with early-onset alcoholism, the significant drinking
reduction and cessation in ondansetron compared with placebo recipients was
due to the efficacy of the pharmacological treatment.

Another study strength was the use of a dose-ranging paradigm, still
a rarity in medications in development for alcoholism.66
Future studies can now focus on testing different treatment options using
ondansetron's most efficacious dosage. Ondansetron was well tolerated and
its adverse event profile was similar to that of placebo.

Pill-taking rates were high (>92%). Although the analyses of percentage
urine riboflavin could have been confounded by dietary changes, including
the intake of multivitamin supplements, its close agreement with the pill
count data would argue that each measure provided validation of the other.
Additionally, use of riboflavin dosages greater than 50 mg/d increases this
measure's reliability since the dosage greatly exceeds that commonly found
in over-the-counter multivitamin preparations.54

Patients with early-onset alcoholism had higher rates of antisocial
personality disorder than patients with late-onset alcoholism. Also, baseline
data from a cohort of the current sample, which are detailed elsewhere, showed
that patients with early-onset compared with late-onset alcoholism have higher
rates of childhood risk behaviors, hostility, impaired social functioning,
and an increased number of male relatives with alcoholism.25
Further, age of onset in the current sample was significantly correlated with
a family history of alcoholism in a male parent or grandparent; that is, the
earlier the subjects' age of onset the greater was the likelihood that they
had either a male parent or grandparent who was an alcoholic (data not shown).
Hence, an early age of onset was associated with a range of variables that
contribute to biological vulnerability toward alcoholism.

Mechanistically, it is intriguing that a selective 5-HT3
receptor antagonist was efficacious for treating patients with early-onset
alcoholism whereas a selective serotonin reuptake inhibitor had failed67 because these classes of compounds have opposite
effects on serotonergic function. Serotonergic function augmentation by a
partial selective serotonin 1A agonist was also an ineffective
treatment for patients with early-onset alcoholism.32
Patients with early-onset alcoholism do not have a simple selective 5-HT deficiency
state. Instead, patients with early-onset alcoholism may be more likely to
possess a high-functioning polymorphic variant of the serotonin transporter68,69 that is more readily damaged by chronic
alcohol consumption.70 As these raphe transporters
are somatodendritic rather than axonal, the net result is a reduced 5-HT firing
rate due to increased self-inhibition.71 We
hypothesize that reduced 5-HT neurotransmission in patients with early-onset
compared with late-onset alcoholism, differentially upregulates postsynaptic
5-HT3 receptors, a blockade of which may account for ondansetron's
differential treatment effectiveness.66,72

Efficacy of such small ondansetron dosages in treating patients with
early-onset alcoholism is consistent with animal studies of its antirewarding
effects on ethanol consumption,11,13,17
and strengthen the proposal that 5-HT3 receptors are an important
site of alcohol's brain effects1 and that chronic
5-HT3 receptor blockade is not associated with neuroadaptation
of mesocorticolimbic dopamine or 5-HT neurons.73

Scientific frustration had grown because promising animal studies66 showing that medications which alter serotonergic
function could attenuate the urge to drink or drinking per se were not confirmed
by clinical trials. Earlier clinical trials with serotonergic agents looked
for their effects on drinking among heterogeneous alcoholic groups. We show
that alcoholic subtypes varying in selective 5-HT function respond differently
to treatment with a specific serotonergic agent. Medication trials specifically
targeting treatment of underlying biological abnormalities in particular alcoholic
subtypes heralds a new vista in the alcoholism field.

Schuckit MA, Mazzanti C, Smith TL.
et al. Selective genotyping for the role of 5-HT2A, 5-HT2C, and GABA alpha
6 receptors and the serotonin transporter in the level of response to alcohol:
a pilot study. Biol Psychiatry.1999;45:647-651.

Figures

Patients diagnosed as having early-onset and late-onset alcoholism
were similar in number, age, sex, and drinking level at enrollment. Trial
completers were those patients who completed all 11 double-blind visits or
10 double-blind visits plus the final physical health evaluation.

Data are responses observed at the start of double-blind (visit 2)
and the mean outcome observed during study (mean of visits 3-12). Analyses
refer to pairwise comparisons between the ondansetron treatment groups and
placebo. The a* and a† represent significant differences between an
ondansetron dosage and placebo groups at the 5% and 1% levels, respectively.
The b* and b† denote significant differences within a given treatment
group from the start of the double-blind response period to the outcome during
study at the 5% and 1% levels, respectively.

Schuckit MA, Mazzanti C, Smith TL.
et al. Selective genotyping for the role of 5-HT2A, 5-HT2C, and GABA alpha
6 receptors and the serotonin transporter in the level of response to alcohol:
a pilot study. Biol Psychiatry.1999;45:647-651.

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